Histone deacetylases (HDAC) constitute an interesting therapeutic target for the treatment of cancer (cf. P. A. Marks et al. Nature Rev. Cancer 2001, 1, 194; J. E. Bolden et al. Nature Rev. Drug Discov. 2006, 5, 769; P. Gallinari et al. Cell Res. 2007, 17, 195; K. B. Glaser Biochem. Pharmacol. 2007, 74, 659; L. Pan et al. Cell. Mol. Immunol. 2007, 4, 337; M. Haberland et al. Nature Rev. Genetics 2009, 10, 32; Y. Zhang et al. Curr. Med. Chem. 2008, 15, 2840; S. Ropero, M. Esteller Mol. Oncol. 2007, 1, 19) and other diseases such as those related to central nervous system (cf. A. G. Kazantsev, L. M. Thompson. Nature Rev. Drug Discov. 2006, 7, 854).
Several families of HDAC inhibitors (HDACis) have been designed, whose general structures can be found in different reviews (cf. A. Villar-Garea, M. Esteller Int. J. Cancer 2004, 112, 171; T. A. Miller et al. J. Med. Chem. 2003, 46, 5097; T. Suzuki, N. Miyata Curr. Med. Chem. 2005, 12, 2867; M. Paris et al. J. Med. Chem. 2008, 51, 1505). The general structure of these inhibitors consists of a cyclic structure, a spacer and a chelating group capable of binding to the Zn (II) cation of the active center of the different HDAC isoforms that belong to the class I (HDAC1, HDAC2, HDAC3 and HDAC8), class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10) and class IV (HDAC11). Despite having a similar inhibition mode, occasionally some selectivity in the inhibition of different HDAC isoforms has been observed (cf. J. C. Wong et al. J. Am. Chem. Soc. 2003, 125, 5586; G. Estiu et al. J. Med. Chem. 2008, 51, 2898). The mentioned selectivity is of therapeutic interest (cf. K. V. Butler, A. P. Kozikowski Curr. Pharm. Design 2008, 14, 505; T. C. Karagiannis, A. El-Osta Leukemia 2007, 21, 61).
Among the chelating groups capable of binding to the Zn cation in the different isoforms of HDAC, several functional groups have been developed, such as, inter alia, carboxylic acids, hydroxamic acids, methyl and trifluoromethyl ketones, epoxides, sulfides and disulfides, o-aminobenzamides, N-hydroxyformyl derivatives, mercaptoamides, sulfones and phosphones (cf. M. Paris et al. op. cit.; T. Suzuki, N. Miyata, op. cit.). As spacer groups that connect the chelating group with the opposite side of the inhibitors, aliphatic linear chains and aromatic and heteroaromatic groups have been described. As examples of HDACis that incorporate aromatic and heteroaromatic spacers the following can be mentioned: Belinostat (PXD101), Panobinostat (LBH-589), CRA-024781, MGDC0103, Entinostat (MS-275, also described as SNDX-275), ITF2357, JNJ-16241199, Tacedinaline (CI-994) and LAQ-824 (cf. M. Paris et al. op. cit. and cited references).
On the other hand, as terminal groups that are on the opposite side of the chelating groups of the inhibitors, several cyclic, heteroaromatic and aromatic systems have been studied (cf. M. Paris et al. op. cit.; T. A. Miller op. cit.; T. Suzuki, N. Miyata op. cit.). In particular, the following groups have been used for this purpose or as spacers: 2,4-substituted-1H-pyrroles, with aroyl groups in position 4 (cf. S. Massa et al. J. Med. Chem. 1990, 33, 2845; S. Massa et al. J. Med. Chem. 2001, 44, 2069; A. Mai et al. J. Med. Chem. 2003, 46, 512) or cinnamoyl groups at the same position (cf. D. Chen et al. Benzimidazole derivatives: Preparation and pharmaceutical applications. WO/2005/028447, 2005; S. Inoue. et al. Cancer Res. 2006, 66, 6785). Likewise, concerning the monosubstituted 1H-pyrroles, the use of N-(7-(hydroxyamino)-7-oxoheptyl)-1H-pyrrol-2-carboxamide as HDACi has been described (cf. Y. Dai et al. Bioorg. Med. Chem. Lett. 2003, 13, 1897). Finally, some of the authors of the present invention have described the synthesis of tri- and tetrasubstituted 1H-pyrroles (cf. A. Arrieta et al. J. Org. Chem. 2007, 72, 4313) as well as their use as terminal groups in the obtention of HDACis (cf. A. Zubia et al. Oncogene 2009, 28, 1477; D. Otaegui et al. Cancer Chemother. Pharm. 2009, 64, 153; D. Otaegui et al. J. Chromatography B 2008, 870, 109; F. P. Cossío et al. Nuevos derivados pirrólicos con actividad inhibidora de desacetilasas de histonas WO/2007/074176, 2005). However, in that case only the activity of inhibitors containing pyrrole rings with linear aliphatic chains as spacers is described. The activity of 3,5-substituted 2-carboxamide-1H-pyrroles connected with the chelating groups through structures containing aromatic or heteroaromatic rings is unknown.
Within this context, the present invention describes the chemical synthesis and the HDACi activity of novel trisubstituted pyrrolic derivatives connected with the chelating groups through aromatic and heteroaromatic groups, that show inhibitory activity against several HDAC isoforms, in particular those belonging to class I and II.